DESCRIPTION (Applicant's Description) It is estimated that between 20-80 percent of patients treated for locally advanced epithelial or mesenchymal tumors will die secondary to the failure of photon therapy and/or surgery to achieve local control. Furthermore, these aggressive local therapies are themselves often associated with significant acute and late morbidity. There are other tumors, particularly pediatric tumors, for which local control is often satisfactory but treatment-related late effects are high. It is the primary aim of this Program Project to exploit the superior dose distributions of proton beams to improve clinical outcomes for patients with a variety of solid tumors both in terms of cancer control and treatment-related morbidity. We have treated over 5,000 cancer patients with proton therapy at the Harvard Cyclotron Laboratory since 1974. We have achieved significant gains in clinical outcomes for a number of disease sites including chondrosarcomas and chordomas of the skull base and cervical spine (95 percent and 50 percent local control, respectively), paranasal sinus tumors (87 percent local control), and ocular melanomas (97 percent local control). We propose to carry out clinical trials using proton beams in additional tumor sites where photon therapy has provided suboptimal treatment outcomes. The two basic hypotheses for this Program Project are that, using the superior dose distributions of proton beams, we can (in subproject 5) escalate tumor dose and improve local control without increasing damage to non-target normal tissues and (in subproject 6) maintain high rates of local control while decreasing treatment related morbidity. We will assess clinical gains in terms of five endpoints: 1) local control, 2) distant metastasis-free survival, 3) overall survival, 4) treatment-related morbidity, and 5) quality-of-life (QOL) We also hypothesize that proton irradiation will decrease the comorbidity between radiation therapy and chemotherapy thus improving compliance and intensity of treatment. We will use well-designed prospective phase I/II/III trials to test these hypotheses. The proposed research program consists of three closely related projects. In subproject 5 we will carry out phase I/II/III dose escalation studies for prostate, lung, paranasal sinus, nasopharynx and hepatocellular cancers. The goals of these trials are to improve local control and survival. In subproject 6 we will carry out phase II/III studies designed to reduce treatment-related morbidity for pediatric cancers including medulloblastoma, retinoblastoma, and soft tissue sarcomas, and adult tumors including rectal carcinoma and choroidal melanoma. In the prostate clinical trial we will collaborate with the Loma Linda University Medical Center in protocol design and patient accrual. In subproject 4 we will develop treatment delivery and planning systems, and design and carry out dosimetry and quality assurance programs to support the proposed clinical trials. The Northeast Proton Therapy Center (NPTC), jointly funded by the NCI and the MGH, has been built on the MGH campus. The NPTC will provide the increased capacity and new technologies needed to conduct the clinical trials proposed in this application. With our experience in conducting proton clinical trials, and the resources offered by the NPTC, we have unique capabilities to carry out the proposed research. It is our expectation that these clinical trials will show improved cancer control rates, reduced treatment morbidity and improved QOL.